History and Defnition

Respiratory bronchiolitis (RB) is a histopathologic lesion, seen in virtually all smokers, that was rst recognized in 1974 on an autopsy series of young cigarette smokers who died of non-pulmonary causes [20]. The histopathologic features are characterized by clusters of brown pigmented macrophages in the rst-order and second-order respiratory bronchioles commonly referred to as “smokers’ macrophages” and “smokers’ bronchiolitis.” [13] Clinically, RB is associated with asymptomatic or a minimally symptomatic disease state characterized by mild cough and/or dyspnea [13–15]. In this scenario it is described as RB associated interstitial lung disease (RB-ILD) which is thought to be a more severe stage in which the alveolar accumulation and bronchiolar infammation extends to the peribronchiolar interstitium [1, 21]. However, some pathologists believe RB cannot be distinguished from RB-ILD by pathological ndings alone requiring the clinical and radiologic ndings to be considered when making the diagnosis [22, 23].

It is important to note that the nomenclature and classi - cation of all smoking-related interstitial pneumonias remains controversial. The 2013 American Thoracic Society and European Respiratory Society statement classi ed RB-ILD and DIP as smoking-related idiopathic interstitial pneumonias (SR-IIP) [3]. RB-ILD and DIP are considered separate, clinically distinguishable entities although some believe they are on a spectrum of disease in which RB-ILD is relatively mild compared to DIP.

Epidemiology

RB-ILD is typically seen in heavy smokers (>30 pack year) in the fourth and fth decades of life with a 2:1 male predominance [1, 24, 25]. However, there are rare reports of RB-ILD seen even in patients with minimal tobacco use, heavy second-hand exposure, or use of electronic cigarettes (vaping.) [23, 26, 27] It is considered a rare disorder although likely underestimated as it may be noted incidentally in the background of other common complications related to heavy smoking. Given the dif culty with distinguishing RB-ILD from RB along with the changing nomenclature landscape of other smoking-related interstitial pneumonias, it remains dif-cult to determine additional epidemiologic features of this disease.

Presentation

The majority of patients present with nonspeci c respiratory complaints including gradual onset of dyspnea and new or changing cough in the setting of tobacco use. Impairment in

functional capacity is generally minimal and overlaps with early emphysema, making the diagnosis dif cult. On exam, inspiratory crackles are the most prominent feature and are generally coarse in nature and occur throughout inspiration and occasionally into exhalation [28]. Rarely, do patients have any clubbing [1, 24, 25, 28].

Diagnostic Evaluation

The pulmonary function testing (PFT) pattern most often seen in RB-ILD is a mixed pattern of obstructive and restrictive physiology. The brosis and infammation of the respiratory bronchioles seen in RB-ILD are similar changes to those in COPD and along with coexisting emphysema are responsible for the obstruction [22]. The interstitial disease causes the restrictive pattern along with impaired gas exchange affecting DLco. A signi cant response to inhaled bronchodilators is not typically seen due to the fact that the pathologic process is not bronchospastic. Overall, the most common PFT abnormality is a decreased DLCO and often times will correlate with disease severity [1, 29]. Approximately 10% of patients have normal lung function at diagnosis [30].

There are no speci c laboratory tests that aid in the diagnosis of RB-ILD. Disease severity can also correlate with imaging ndings.

Radiology

Although there are no pathognomonic imaging ndings associated with RB-ILD, common imaging patterns are seen. Chest radiography often appears normal but can have abnormalities such as thickening of the walls of the central or peripheral bronchi and ne reticulonodular opacities, typically diffuse or upper lung predominant [1, 24, 28]. HRCT is more clinically useful and frequently shows nonspeci c changes such as centrilobular nodularity and patchy GGO with septal thickening (Fig. 34.4). The radiographic differential includes hypersensitivity pneumonitis and nonspeci c interstitial pneumonia (NSIP) [31]. Since all of these patients are smokers or former smokers, concomitant emphysema is common as well.

Histopathology

As diagnostic uncertainty typically remains after detailed history and imaging review, the next step in the work-up of RB-ILD often includes a bronchoscopy, as is the case with many ILDs. In the case of suspected RB-ILD, bronchoscopy is not typically helpful but may assist in ruling out other

ILDs. The vast majority of BAL samples are ­indistinguishable from lavage fuid from otherwise healthy smokers (increased cells with normal differential). One difference seen in RB-ILD is that there are a relatively higher amount of pigmented macrophages compared to healthy nonsmoking individuals [1, 29]. This nding is nonspeci c and may be seen other smoking-related lung diseases. A surgical lung biopsy is required to see de nitive patterns of RB-ILD although there remains debate as to whether RB and RB-ILD can be fully elucidated by histopathological criteria even with surgical specimens. At present, clinical correlation remains important [21, 32].

Fig. 34.4  High-resolution computed tomography images from a patient with respiratory bronchiolitis interstitial lung disease demonstrating areas of faint, patchy ground glass opaci cation, and reticular thickening

Histopathologically, RB-ILD generally differs from RB by demonstrating brous scarring that extends into the surrounding alveolar wall in addition to the aforementioned clusters of pigmented macrophages [22, 25]. These clusters are more frequently found near the bronchioles as compared to the rest of the lung parenchyma. In addition, these clusters are more prominent than those seen in healthy cigarette smokers [28]. Caution must be used in distinguishing RB from hemosiderin which may be found in diffuse alveolar hemorrhage or chronic passive congestion due to heart failure which are both highlighted in stains such as Prussian blue and depend on keen pattern recognition of the neness and distribution by an experienced histopathologist [32]. RB-ILD lacks features of usual interstitial pneumonia (UIP) such as honeycombing and broblastic foci. Concomitant emphysema may be seen as well in RB and RB-ILD, owing to the strong association with smoking [22] (Fig. 34.5).

Clinical Course

The natural history of RB-ILD is dif cult to ascertain as it is very rare. Previous studies are conficted as to whether patients worsen, improve, or stabilize regardless of smoking status. Initial studies suggested that it was a benign disease process, however, more recent studies suggest that RB-ILD has a more sinister course [29, 33–35]. Additionally, there are reports of a disconnect between the patient’s described sense of stable or improved dyspnea and objective measurements of validated dyspnea scores which clearly worsened over the same time [29]. There have been no deaths reported due to RB-ILD.

Fig. 34.5  The main histologic nding of respiratory bronchiolitis interstitial lung disease is similar to that of desquamative interstitial pneumonia, namely increased numbers of intra-alveolar macrophages (panel a). This process is limited to the small bronchioles and peribronchiolar airspaces (arrowhead panel b) in respiratory bronchiolitis inter-

stitial lung disease and is more diffuse in desquamative interstitial pneumonia, although no quantitative histologic criteria have been established. Histologically, desquamative interstitial pneumonia and respiratory bronchiolitis interstitial lung disease likely represent the ends of a continuum of smoking-related disease